TY - JOUR

T1 - Comparative study of the steroidogenic effects of human chorionic gonadotropin and thieno[2,3-d]pyrimidine-based allosteric agonist of luteinizing hormone receptor in young adult, aging and diabetic male rats

AU - Bakhtyukov, Andrey A.

AU - Derkach, Kira V.

AU - Gureev, Maxim A.

AU - Dar’in, Dmitry V.

AU - Sorokoumov, Viktor N.

AU - Romanova, Irina V.

AU - Morina, Irina Yu

AU - Stepochkina, Anna M.

AU - Shpakov, Alexander O.

N1 - Bakhtyukov, A.A.; Derkach, K.V.; Gureev, M.A.; Dar’in, D.V.; Sorokoumov, V.N.; Romanova, I.V.; Morina, I.Y.; Stepochkina, A.M.; Shpakov, A.O. Comparative Study of the Steroidogenic Effects of Human Chorionic Gonadotropin and Thieno[2,3-D]pyrimidine-Based Allosteric Agonist of Luteinizing Hormone Receptor in Young Adult, Aging and Diabetic Male Rats. Int. J. Mol. Sci. 2020, 21, 7493.

PY - 2020/10/2

Y1 - 2020/10/2

N2 - Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino-N-tert-butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats. Type 1 diabetes was caused by a single streptozotocin (50 mg/kg) injection. TP4/2 (20 mg/kg/day) and hCG (20 IU/rat/day) were administered for 5 days. TP4/2 was less effective in adenylyl cyclase stimulation and ability to activate steroidogenesis when administered once into rats. On the 3rd–5th day, TP4/2 and hCG steroidogenic effects in young adult, aging and diabetic rats were comparable. Unlike hCG, TP4/2 did not inhibit LHCGR gene expression and did not hyperstimulate the testicular steroidogenesis system, moderately increasing steroidogenic proteins gene expression and testosterone production. In aging and diabetic testes, TP4/2 improved spermatogenesis. Thus, during five-day administration, TP4/2 steadily stimulates testicular steroidogenesis, and can be used to prevent androgen deficiency in aging and diabetes.

AB - Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino-N-tert-butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats. Type 1 diabetes was caused by a single streptozotocin (50 mg/kg) injection. TP4/2 (20 mg/kg/day) and hCG (20 IU/rat/day) were administered for 5 days. TP4/2 was less effective in adenylyl cyclase stimulation and ability to activate steroidogenesis when administered once into rats. On the 3rd–5th day, TP4/2 and hCG steroidogenic effects in young adult, aging and diabetic rats were comparable. Unlike hCG, TP4/2 did not inhibit LHCGR gene expression and did not hyperstimulate the testicular steroidogenesis system, moderately increasing steroidogenic proteins gene expression and testosterone production. In aging and diabetic testes, TP4/2 improved spermatogenesis. Thus, during five-day administration, TP4/2 steadily stimulates testicular steroidogenesis, and can be used to prevent androgen deficiency in aging and diabetes.

KW - Aging rats

KW - Diabetes mellitus

KW - Human chorionic gonadotropin

KW - Low-molecular-weight agonist

KW - Luteinizing hormone receptor

KW - Spermatogenesis

KW - Steroidogenesis

KW - Testes

UR - http://www.scopus.com/inward/record.url?scp=85092462739&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/1f4a890d-fa14-380c-a726-c896fdc7f30c/

U2 - 10.3390/ijms21207493

DO - 10.3390/ijms21207493

M3 - Article

C2 - 33050653

AN - SCOPUS:85092462739

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 20

M1 - 7493

ER -